WO2002092125A1 - Compositions permettant de traiter les troubles associes aux ige - Google Patents

Compositions permettant de traiter les troubles associes aux ige Download PDF

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Publication number
WO2002092125A1
WO2002092125A1 PCT/EP2001/005412 EP0105412W WO02092125A1 WO 2002092125 A1 WO2002092125 A1 WO 2002092125A1 EP 0105412 W EP0105412 W EP 0105412W WO 02092125 A1 WO02092125 A1 WO 02092125A1
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WIPO (PCT)
Prior art keywords
composition
ige
antigen
subject
activity
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PCT/EP2001/005412
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English (en)
Inventor
Thomas Hultsch
Jens Brauburger
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
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Publication date
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Priority to CA002446108A priority Critical patent/CA2446108A1/fr
Priority to EP01940460A priority patent/EP1390067A1/fr
Priority to US10/476,263 priority patent/US20050031609A1/en
Priority to CNA018232426A priority patent/CN1507353A/zh
Priority to JP2002589041A priority patent/JP2004529180A/ja
Priority to PCT/EP2001/005412 priority patent/WO2002092125A1/fr
Priority to BR0117009-0A priority patent/BR0117009A/pt
Publication of WO2002092125A1 publication Critical patent/WO2002092125A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • C07K16/4291—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention provides methods of treating IgE-associated disorders and products for use therein.
  • the methods are particularly useful in treatment of allergies such as allergic rhinitis.
  • Hypersensitivity reactions involve humoral mediators such as interleukins and interferons, complement proteins, and immunoglobulins.
  • humoral mediators such as interleukins and interferons, complement proteins, and immunoglobulins.
  • interleukins and interferons include interleukins and interferons, complement proteins, and immunoglobulins.
  • complement proteins include interleukins and interferons, complement proteins, and immunoglobulins.
  • immunoglobulins One of the most common pathologic features of allergic conditions is the presence of inflammation caused by activation of the immune system.
  • an individual For an allergic reaction to occur, an individual must have had prior exposure to an allergen. Following the initial antigen exposure, the immune system produces IgE specific for the inciting antigen. The antigen-specific IgE then binds to mast cell membranes via IgE receptors. When re-exposed to the antigen, the antigen-specific IgE antibody binds to the antigen and activates the mast cells. Such mast cell activation causes a release of vasoactive and neuronal stimulatory mediators such as histamines, leukotrienes, prostaglandins, bradykinin, and platelet-activating factor and inflammatory mediators such as eosinophils, basophils, neutrophils, and CD4 T-lymphocytes.
  • vasoactive and neuronal stimulatory mediators such as histamines, leukotrienes, prostaglandins, bradykinin, and platelet-activating factor and inflammatory mediators such as eosinophils, basophils
  • Allergic rhinitis is a clinical disorder characterized by nasal congestion, rhinorrhea, sneezing, and itching. Severity of these symptoms can vary from year to year, with occasional spontaneous remissions. Therefore, allergic rhinitis is classified by whether symptoms occur during certain seasons (SAR or seasonal allergic rhinitis) or year- round (PAR or perennial allergic rhinitis). The seasonal variety is usually caused by pollens from plants that depend on the wind for cross-pollination, such as grasses, trees, weeds, and mold spores.
  • Serious complications can occur if allergic rhinitis is not treated or is undertreated.
  • Psychosocial effects can include frequent absences from work or school, poor performance, poor appetite, malaise, and chronic fatigue.
  • Allergic asthma as a clinical disorder that is characterized by three components: airway inflammation; airway obstruction, which is reversible; and increased sensitivity, referred to as hyperreactivity.
  • Obstruction to airflow is measured by a decrement in forced expired volume in one second (FEV I) which is obtained by comparison to baseline spirometry.
  • FEV I forced expired volume in one second
  • Hyperreactivity of the airways is recognized by decreases in FEVI in response to very low levels of histamine or methacholine. Hyperreactivity may be exacerbated by exposure of the airways to allergen.
  • an optimal treatment for allergy would reduce or remove the symptoms and also correct the immune system's abnormal reactions.
  • Use of symptomatic drugs such as antihistamines or steroids can reduce symptoms, but they do not deal with the underlying disease.
  • Specific immunotherapy which is also known as specific allergy vaccination, desensitization or hyposensibilisation, is a treatment option that interferes with the basic mechanisms of the allergic disease.
  • Specific immunotherapy is used for respiratory allergies - e.g. tree pollens, grass pollens, animal dander, moulds and house dust mites. It is also effective as protection against severe allergic reactions to bee and wasp stings.
  • Regular vaccination with minute quantities of the offending allergen in gradually increasing doses stimulates the immune system to develop an increased tolerance.
  • the present invention now provides a method of treating a subject having an IgE associated disorder comprising administering to the subject an amount of a first composition comprising an immunogenie antigen and administering to the subject an amount of a second composition that inhibits the activity of IgE.
  • compositions that inhibits the activity of IgE for the manufacture of a medicament for the treatment of a subject having an IgE associated disorder, wherein the subject is treated simultaneously or sequentially with a composition comprising an immunogenie antigen.
  • products which contain a composition comprising an immunogenie antigen and a composition that inhibits the activity of IgE as a combined preparation for simultaneous, separate or sequential us in the therapy of an IgE associated disorder.
  • compositions that inhibits the activity of IgE are also within the scope of this invention.
  • a pharmaceutical formulation comprising a composition that inhibits the activity of IgE and a composition comprising an immunogenie antigen.
  • a method of treating an allergic response to an antigen or allergy- related disorder during antigen-specific immunotherapy of a subject comprising administering to the subject an amount of a first composition that inhibits the activity of IgE sufficient to decrease the activity of IgE in the subject and administering to the subject a second composition comprising an amount of the antigen sufficient to modulate the immune response to the antigen.
  • the present invention provides novel methods of treating a subject having an IgE associated disorder.
  • This combination method comprises administering to the subject an amount of a first composition comprising an immunogenie antigen and administering to the subject an amount of a second composition that inhibits the activity of IgE.
  • treatment includes alleviation of one or more symptoms of the disorder, diminishment of the extent of the disorder, stabilization of the disorder, delay or slowing of disorder progression, amelioration or palliation of the disorder, and partial or total remission. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • the methods of the invention are appropriate for prevention of an allergic response as well as treating a pre-existing allergic condition.
  • the method of treatment of the invention particularly relates to clinical methods known as specific immunotherapy or desensitization.
  • Specific immunotherapy refers to the process of administering increasing doses of an antigen, such as, in particular, an allergen to which the subject has demonstrated sensitivity.
  • an antigen such as, in particular, an allergen to which the subject has demonstrated sensitivity.
  • allergen doses used for desensitization are known in the art and are further described in the Examples hereinbelow.
  • the treatment provided by the present invention may be short-term pre- seasonal treatment or may last for several years, as, for example, with vaccinations in alternate months.
  • the first and second compositions of the invention can, for example, be given as injections. It is also possible to place the allergen extract as small drops under the tongue, for example, two to three times a week.
  • the immune system responds there may still be need to continue with the medication.
  • the need for drugs will decrease as the symptoms will become less severe.
  • the effect may be maintained for several years, in particular up to 5-10 years or more, after the treatment has been completed.
  • the natural aggravation of the allergic disease may be inhibited and the development of asthma and/or new allergies may be prevented by the method of treatment according to the invention.
  • IgE associated disorder within the meaning of the invention is a condition which is characterized by elevated IgE levels.
  • the elevated IgE levels may or may not be persistent.
  • IgE associated disorders include, but are not limited to, allergy and allergic reactions, asthma, rhinitis, conjunctivitis, urticaria, shock, hymenoptera sting allergies, drug allergies, and parasite infections. The term also includes related manifestations of these disorders.
  • the IgE associated disorder is an allergy
  • An allergy is a disorder characterized by an allergic response to antigen, in particular it is characterized by the generation of antigen-specific IgE and the resultant effects of the IgE antibodies.
  • IgE binds to IgE receptors on mast cells and basophils. Upon later exposure to the antigen recognized by the IgE, the antigen cross- links the IgE on the mast cells and basophils causing degranulation of these cells.
  • allergy is allergic asthma, allergic rhinitis, and, in particular, perennial allergic rhinitis (PAR) and seasonal allergic rhinitis (SAR).
  • SAR is a particularly preferred indication for treatment by the methods of the invention.
  • the IgE associated disorder is SAR in patients having an age of 6-17 years. Also preferred are young patients having an age of 6-12 years, 6-10 and 6-8 years. Also preferred are patients having a clinical history below 2 years of moderate to severe SAR. Furthermore, preferred are patients having a serum IgE level between 30 and 1300 lU/ml.
  • Seasonal allergic rhinitis is a form of allergic rhinitis that shows seasonal variety. In contrast, in perennial allergic rhinitis, symptoms occur throughout the year. However, a pollen allergy can contribute to seasonal exacerbations of rhinitis in patients with perennial symptoms.
  • immunogenie antigen means a substance that is recognized and bound specifically by an antibody or by a T cell antigen receptor. Such an antigen may preferredly be an allergen as defined hereinbelow.
  • Haptens are immunogenie antigens within the meaning of the invention.
  • a hapten is a low molecular weight compound that is not immunogenie by itself but is rendered immunogenie when conjugated with an immunogenie molecule containing antigenic determinants.
  • the antigen is capable of eliciting or modulating an immune response in a human being as measured by techniques know in the art.
  • Such tests of immune responses are known to the person skilled in the art, in particular skin tests and tests specifically assaying the IgE levels are useful to quantify an immune response.
  • An immune response is elicited if there was no prior immune response to said antigen, it is modulated if it significantly changes as measured by the respective test. A change may be significant for example if increased or decreased by at least 10%, 20%, 50% or even 2 fold.
  • Immunogenie antigens capable of eliciting or modulating an immune response in a human being generally can include peptides, proteins, glycoproteins, polysaccharides, gangliosides and lipids; portions thereof and combinations thereof.
  • the antigens can be those found in nature or can be synthetic.
  • the antigen is an allergen.
  • allergen means an antigen or antigenic portion of a molecule which elicits an allergic response upon exposure to a subject.
  • the subject is allergic to the allergen as can be measured by clinical tests, assessed by taking the clinical history of the subject or any other suitable method known in the art and as further described in the Examples hereinbelow.
  • An antigen is said to be an allergen if only a small subset of subjects exhibit an immune response upon exposure to the molecule.
  • Numerous isolated allergens are known in the art. For example, common allergens in patients with seasonal allergic rhinitis include pollen from grasses, trees, weeds and mold spores. Common allergens in patients with perennial allergic rhinitis are household dust mites, wood dust, molds, fungus spores, feather pillows, animal dander, animal hair, and cigarette smoke, the most
  • the allergen is an aeroallergen.
  • the aeorallergen is a grass pollen allergen, such as for example ALK SQ as further described in the Examples hereinbelow.
  • allergens are, for example, bee-venom extracts, dust mite extracts and rhagweed extracts.
  • a composition that inhibits the activity of IgE is a composition that contains at least one agent that reduces IgE activity when compared to otherwise same conditions, except for the absence of the composition.
  • IgE activity may be measured by the circulating levels of IgE, but can also be measured by activities associated with IgE function, such as binding to basophils, anaphylaxis, and binding to receptors such as Fc receptors.
  • compositions that inhibit the activity of IgE may include, for example, anti-lgE antibodies, IgE receptors, anti-lgE receptor antibodies, variants of IgE antibodies, ligands for the IgE receptors, and fragments thereof.
  • Variant IgE antibodies may have amino acid substitutions or deletions at one or more amino acid residues.
  • the composition that inhibits the activity of IgE comprises an anti-lgE antibody.
  • the anti-lgE antibody is a humanized murine antibody or a fully human antibody.
  • the anti-lgE antibody is Omalizumab, which is also named "E25”.
  • Another preferred anti-lgE antibody is named "E26" as further defined hereinbelow.
  • Anti-lgE antibodies are described in the prior art, and in greater detail in the International applications WO 93/04173 and WO 99/01556.
  • WO 99/01556 specifically describes Omalizumab, also named E25, in Figure 12, and in the sequences ID-No. 13- 14.
  • Antibody molecules comprising a E26 sequence are described in WO 99/01556 and are selected from the group of F(ab) fragment (Sequence ID Nos. 19-20), sFv fragment (Sequence ID No. 22) and F(ab)' 2 fragment (Sequence Nos. 24-25), in accordance to Figures 12-15.
  • the terms E25 and E26 shall be construed accordingly.
  • the IgE antibodies of the instant invention do not result in histamine release from mast cells or basophils.
  • U.S. Patent 5,449,760 generally describes anti-lgE antibodies that bind soluble IgE but not IgE on the surface of B cells or basophils. Antibodies such as these bind to soluble IgE and inhibit IgE activity by, for example, blocking the IgE receptor binding site, by blocking the antigen binding site and/or by simply removing the IgE from circulation. Additional anti- IgE antibodies and IgE-binding fragments derived from the anti-lgE antibodies are described in U.S. Patent 5,656,273. U.S. Patent 5,543,144 describes anti- IgE antibodies that bind soluble IgE and membrane-bound IgE on IgE- expressing B cells but not to IgE bound to basophils.
  • compositions of the invention are administered in therapeutic amounts.
  • therapeutic amount generally denotes an amount that prevents or ameliorates symptoms of a disorder or responsive pathologic physiological condition.
  • the allergen is administered in an amout sufficient to induce desensitization to the allergen in combination with the composition that inhibits the activity of IgE. This amount may or may not be an amount that is therapeutic in the absence of the composition that inhibits the activity of IgE.
  • the "therapeutic amount" of a substance or composition depends upon the context in which it is being applied. In the context of administering a composition that inhibits IgE activity, a therapeutic amount is an amount sufficient to achieve any such inhibition, which need not be total.
  • a therapeutic amount can be administered in one or more administrations, and it is understood that, especially in the context of allergy desensitization therapy, a therapeutic amount is achieved over a series of administrations, typically in increasing dosages.
  • the median symptom load is reduced by at least 10%, preferredly by at least 20% or even by at least 40%.
  • the symptom load is the mean daily symptom score plus mean daily rescue medication score as defined in the Examples below.
  • the days with intake of any allergy medication are reduced by at least 10%, preferredly by at least 20% or even by at least 60%. For example, such reduction can be achieved in the birch and/or in the grass pollen season.
  • the median use of rescue medication is reduced by at least 10%, preferredly by at least 20% or even by at least 60%. Most preferred is a reduction above 70%. For example, such reduction can be achieved in the birch and/or in the grass pollen season.
  • the first and second compositions can be administered to the subject in a pre-determined order or/and simultaneously.
  • the first composition including the antigen may be administered before the second composition.
  • the first composition is administered with the second composition.
  • the present invention also provides for a method wherein in a first treatment period the first composition is titrated up to a maintenance dose, and in a second treatment period the second composition is administered in addition to the maintenance dose of the first composition.
  • the first treatment period may be about 12 weeks and the second treatment period may be about 24 weeks.
  • the first treatment period is started at least 14 weeks prior to the relevant allergen season, such as for example the relevant pollen season. Preferredly, there is no time interval between the two treatment periods.
  • Suitable surrogate markers are, for example, leukotriens, markers for the activation of mast cells, such as, for example, tryptase, and eosinophil counts.
  • the present invention also provides products containing a composition comprising an immunogenie antigen and a composition that inhibits the activity of IgE as a combined preparation for simultaneous, separate or sequential use in the therapy of an IgE associated disorder.
  • the active ingredients described in any of the embodiments herein may be combined into a single composition for simultaneous administration of one or more of the active ingredients.
  • the present invention also provides a pharmaceutical formulation comprising a composition that inhibits the activity of IgE and a composition comprising an immunogenie antigen.
  • a pharmaceutical formulation comprising a composition that inhibits the activity of IgE and a composition comprising an immunogenie antigen.
  • Such a formulation will be prepared according to methods know in the art and will dependent on the nature of the active agents in the first and second composition.
  • such formulations may advantageously include buffering agents, preservatives, stabilizers, and non-ionic surfactants or detergents.
  • Buffering agents help to maintain the pH in the range which approximates physiological conditions. They are preferably present at concentration ranging from about 2mM to about 50 mM.
  • Suitable buffering agents for use with the present invention include both organic and inorganic acids and salts thereof such as citrate buffers (e.g., monosodium -citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid- monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodiurn succinate mixture, etc.).
  • citrate buffers e.g., monosodium -citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid- monosodium citrate mixture, etc.
  • succinate buffers e.g., succinic acid-monoso
  • tartrate buffers e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.
  • fumarate buffers e.g., furnaric acid-monosodiurn fumarate mixture, etc.
  • fumarate buffers e.g., fumaric acid-monosodium famarate mixture, furnaric acid-disodiurn fumarate mixture, monosodium fumarate- disodium fumarate mixture, etc.
  • gluconate buffers e.g., gluconic acid- sodium glyconate mixture, gluconic acid-sodium hydroxide mixture, gluconic acid-potassium glyuconate mixture, etc.
  • oxalate buffer e.g., oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture,
  • Preservatives are added to retard microbial growth, and are added in amounts ranging from 0.2% - 1 % (w/v).
  • Suitable preservatives for use with the present invention include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, octadecyl dimethylbenzyl ammonium chloride, benzalconium halides (e.g., chloride, bromide, iodide), hexamethonium chloride, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.
  • Isotonicifiers sometimes known as “stabilizers” are present to ensure isotonicity of liquid compositions of the present invention and include polhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • Polyhydric alcohols can be present in an amount between 0.1% to 25% by weight, preferably 1 % to 5% taking into account the relative amounts of the other ingredients.
  • Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the therapeutic agent or helps to prevent denaturation or adherence to the container wall.
  • Typical stabilizers can be polyhyric sugar alcohols (enumerated above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, omithine, L- leucine, 2-phenylaianine, glutamic acid, threonine, etc., organic sugars or sugar alcohols, such as lactose, trehalose.
  • cyditols such as inositol; polyethylene glycol; amino acid polymers; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, cc-monothioglyceroi and sodium thio sulfate; low molecular weight polypeptides (i.e.
  • proteins such as human serum albumin, bovine serum albumin, gelatin or immunoglobulins
  • hydrophylic polymers such as polyvinylpyrrolidone monosaccharides, such as xylose, mannose, fructose, glucose; disaccharides such as lactose, maltose, sucrose and trisaccacharides such as raffmose; polysaccharides such as dextran.
  • Stabilizers are present in the range from 0. 1 to 10, 000 weights per part of weight active protein.
  • Non-ionic surfactants or detergents are present to help solubilize the therapeutic agent as well as to protect the therapeutic protein against agitation-induced aggregation, which also permits the formulation to be exposed to shear surface stressed without causing denaturation of the protein.
  • Suitable non-ionic surfactants include polysorbates (20, 80, etc.), polyoxamers (184, 188 etc.), Pluronice polyols, polyoxyethylene sorbitan monoethers (TweenO-20, TweenO-80, etc.).
  • Non-ionic surfactants are present in a range of about 0.05 mg/ml to about 1 1 mg/mL preferably about 0.07 mg/ml to about 0.2 mg/ml.
  • Additional miscellaneous excipients include bulking agents, (e.g. starch), chelating agents (e.g. EDTA), antioxidants (e.g., ascorbic acid, methionine, vitamin E), and cosolvents.
  • the formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desireable to further provide an immunosuppressive agent.
  • Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
  • the active ingredients may also be entrapped in microcapsule prepared, for example, by coascervation techniques or by interfacial polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsule and poly-(methylmethacylate) microcapsule, respectively, in colloidal drug delivery systems (for example, liposomes, albumin micropheres, microemulsions. nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin micropheres, microemulsions. nano-particles and nanocapsules
  • macroemulsions for example, Remington ⁇ Pharmaceutical Sciences, 16th edition, A. Osal, Ed. (1980).
  • the formulations to be used for in vivo administration must be sterile. This is readily accomplished, for example, by filtration through sterile filtration membranes.
  • Sustained-re lease preparations may be prepared. Suitable examples of sustained-re lease preparations include semi-permeable matrices of solid hydrophobic polymers containing the antibody mutant, which matrices are in the Am of shaped articks, e.&, fikv or microcapsules. Examples of sustained-release matrices include polyesters, hydmgels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat.
  • copolymers of L-glutamic acid and ethyl-L- glutamate non-degradable ethylene-vinyl acetate
  • degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)
  • poly-D- (+3- hydroxybutyric acid While polymers such as ethylene-vinyl acetate and lactic acid- glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.
  • encapsulated antibodies When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37'C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, iyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.
  • compositions that inhibits the activity of IgE for the manufacture of a medicament for the treatment of a subject having an IgE associated disorder, wherein the subject is treated simultaneously or sequentially with a composition comprising an immunogenie antigen.
  • this invention also provides a method of treating an allergic response to an antigen or allergy- related disorder during antigen-specific immunotherapy of a subject comprising administering to the subject an amount of a first composition that inhibits the activity of IgE sufficient to decrease the activity of IgE in the subject and administering to the subject a second composition comprising an amount of the antigen sufficient to modulate the immune response to the antigen.
  • the composition that inhibits the activity of IgE comprises an anti-lgE antibody.
  • a composition comprising an antigen for use in immunotherapy according to this method , wherein the antigen is at a concentration higher than acceptable for use in allergy desensitization therapy.
  • a kit comprising this composition in suitable packaging.
  • EXAMPLE 1 Omalizumab combined with specific immune therapy (SIT) in seasonal allergic rhinitis
  • Study D01 was a phase III, placebo-controlled, multicenter, clinical study. Children and adolescents with sensitization to birch and grass pollens suffering from seasonal allergic rhinitis were randomized into four groups: either birch or grass pollen SIT (SIT- birch; SIT-grass) in combination with either omalizumab or placebo. Treatment was started in winter 1999 and was continued during the 2000 pollen season by subcutaneous injections. Dosage of omalizumab was adjusted depending on baseline IgE level and body weight.
  • omalizumab administered using the same dosing scheme as for allergic asthma (based on patient's baseline total IgE level and body weight) was safe and effective for the treatment of SAR and for the combination with SIT.
  • Omalizumab reduced the symptoms of SAR (nose and eyes), the use of rescue medication (topical and systemic) significantly over SIT alone, which is currently best medical practice. Consequently, the symptom load (prim, efficacy endpoint: mean daily symptom score plus mean daily rescue medication score) was reduced significantly in the SIT plus omalizumab group versus SIT alone group.
  • Omalizumab was well tolerated and showed an excellent safety profile over the 24 weeks treatment period. No case of anaphylaxis or an anaphylactoid reaction was observed. There was no significant incidence of urticaria in any treatment group. In vitro assays provide additional evidence for suppression of allergic reaction in vivo (tryptase, ECP).
  • Study D01 was a 36-week double blind, placebo-controlled, randomized, multi-center, parallel group study.
  • the study enrolled a total of 225 patients age 6 - 17 years.
  • the safety sample consists of 222 patients, of which 132 belonged to the age group 6-12 years.
  • one patient received study medication only once and discontinued the study thereafter before start of birch pollen season and before any measurement of efficacy parameter this patient was excluded from the intent-to-treat (ITT) sample.
  • ITT intent-to-treat
  • SIT current standard therapy
  • SIT therapy was administered to all patients, for either birch or grass according to the instructions of the manufacturer.
  • omalizumab or placebo was added for 24 weeks at the dose resulting from the asthma-dosing table as described hereinbelow.
  • Safety was assessed for the 24-week omalizumab treatment period; efficacy was assessed for the pollen seasons as defined by pollen counts locally.
  • the entire pollen season was defined as the first day of the birch pollen season until the last day of the grass pollen season. If there was an intermediate interval between both pollen seasons this interval was excluded from the entire pollen season, i.e. the entire pollen season was the interval from the first day of the birch pollen season until the last day of this season and the interval of the first day of the grass pollen season until the last day in this season.
  • Patients were randomized to receive SIT for either birch or grass pollen beginning treatment at least 14 weeks prior to the pollen season. Additionally, patients received either subcutaneous omalizumab or placebo for 24 weeks during the entire birch and grass pollen season. Daily symptom scores (nose and eyes) and rescue medication usage (antihistamines, corticosteroids) were assessed.
  • the patient population included children and adolescents aged 6 -17 years who suffered from moderate to severe symptoms of SAR. Patients had to meet the following inclusion criteria: (a) serum IgE levels between 30-1300 lU/ml, (b) Positive IgE reactivity (CAP > 2) for birch and grass pollen, (c) clinical history of 2 or more years of moderate to severe SAR (birch and grass).
  • Patients must be asymptomatic or minimally symptomatic during the month before the start of the birch pollen season. Patients could be minimally symptomatic during hazel or alder pollen seasons.
  • Baseline FEV-1 > 70% of the predicted normal value for the patient within 3 month prior to or at randomization. This criterion for FEV-1 must be demonstrated 6 or more hours after short-acting beta-2-agonist use or 72 hours or more after long- acting beta-2-agonist use
  • Patients must have a baseline serum IgE level > 30 lU/ml and ⁇ 1300 lU/ml and a corresponding body weight 7. Patients must meet pretrial eligibility requirements for trial enrollment (acceptable medical history, physical examination results, and acceptable laboratory test results)
  • DNCG cromolyn sodium
  • nedocromil sodium inhaled, nasal or eye drops
  • rhinitis Perennial non-allergic rhinitis, topical or systemic rhinitis medicamentosa, vasomotor rhinitis, structurally related disease (for example, severe deviated nasal septum)
  • beta-adrenergic antagonist medications regularly (e.g., propranolol)
  • antihistamines e.g. chlorpheniramine, acrivastine, promethazine, tripelennamine, diphenhydramine, terfenadine, fexofenadine or other "short-acting" antihistamines, hydroxyzine, loratadine, clemastine or long-acting antihistamines, i.e. astemizole
  • Zyrtec® Cetirizine
  • Livocab® levocabastine hydrochloride
  • Efficacy parameter scores Mean and median daily symptom scores were calculated based on the patient's diary assessment of clinical symptoms. Symptoms were categorized into 7 domains (stuffy nose, runny nose, itchy nose, sneezing and itchy eyes, watery eyes, red eyes). Each category could score 0-3 (none-mild-moderate- severe). Daily rescue medication scores given were: 0 for no medication; 1 for topical antihistamines; 2 for systemic antihistamines, 3 for oral or topical corticosteroids. Only maximal score per day was assessed.
  • Efficacy parameter endpoints The primary outcome variable was the symptom load (mean daily symptom score plus mean daily rescue medication score).
  • the secondary clinical efficacy variables measured were: symptom score (mean of the daily symptom score), rescue medication score (mean of the daily rescue medication score during entire pollen season), proportion of days with rescue and/or concomitant medication use, investigator's global evaluation of treatment tolerability.
  • rhuMAb-E25 is supplied as a sterile, freeze dried preparation that can be reconstituted to a final rhuMAb-E25 concentration of 125 mg/ml.
  • Each 10 ml vial contains 208 mg rhuMAb-E25.
  • rhuMAb-E25 must be stored refrigerated at (2°-8°C) until time of administration to the subject, do not freeze.
  • Each vial is reconstituted with 1.3 ml of Sterile Water for Injection (SWI), and the contents are gently swirled for 30 seconds, then left for up to 5 minutes to solubilize. 1.2 ml is then drawn up to deliver 150 mg of rhuMAb-E25.
  • the formulation does not contain a preservative and is to be used for single-dose administration only.
  • patients randomized to rhuMAb-E25 receive blinded test drug administered on a two or four weekly basis, dependent on baseline IgE levels.
  • the corresponding placebo group receive placebo on a two or four weekly basis, dependent on IgE levels.
  • rhuMAb-E25 is administered using a disposable 25 gauge needle and a disposable plastic tuberculin-type syringe.
  • the injections are administered in the deltoid region on the right arm. Alternately, the injections can be administered in the right thigh if medically significant reasons preclude administration in the deltoid region.
  • the injections are administered subcutaneously.
  • the SIT hazel/alder/birch or grass/rye is titrated with ALK SQ up to the maintenance dose within 12 weeks followed by 4-weekly maintenance dose until the end of grass season.
  • the dose may be adjusted as judged by the investigator according to the guidelines from ALK. After loading SIT into a tuberculin-type syringe SIT is matching to each other.
  • Dose interval and number of doses 12 weeks of SIT titration with allergens from ALK is adequate to increase allergen doses to maintenance dose according to current guidelines of ALK for SIT.
  • the dose of rhuMAb-E25 which is based on baseline free serum IgE levels, is designed to suppresses free serum IgE to levels below 25 ng/ml.
  • the data from previous trials have shown a significant reduction of symptoms in allergic patients when baseline serum free IgE levels were at or below 25 lU/ml. No modification in the drug concentration to suppression relationship was shown to occur after repeated dosing but baseline IgE concentration was identified as an important factor influencing dose.
  • Efficacy of omalizumab treatment in this study population translates clinically in reduction of rescue medication intake (antihistamines and corticosteroids) and/or reduction of clinical symptoms.
  • the median symptom load for patients treated with omalizumab was 48 % lower than for patients treated with placebo (median 0.39 vs. 0.75, p ⁇ 0.001 ; Figure 1). The same pattern appeared for symptom score and rescue medication score. The response in the sub-group aged 6 - 12 ys was comparable to that in the analysis of all patients.
  • Table 6 Markers of activation of mast cells (tryptase) and eosinophils (ECP).
  • Treatment was well tolerated compared to SIT alone. In particular no case of anaphylaxis, generalized urticaria or wheezing following injection appeared. Injection site reactions were not different in both groups, SIT alone or SIT plus omalizumab. Localized urticaria were reported in 2 instances, both occurring in the omalizumab group. Both were of moderate severity. One was judged to be non-study drug related and resulted in treatment with systemic antihistamine (cetirizine). One case was considered to be study drug related, lasted 24 hr. and ceased without additional treatment.
  • AEs adverse events
  • treatment emergent AE i.e. start of AE at day of or after date of first administration of omalizumab/placebo
  • placebo group 79.63% of patients
  • omalizumab group 79.82% of patients
  • the most frequently affected body systems >5% of patients in either treatment group
  • Table 7 and 8 The differences in frequency between the two treatments were small, with the exception of nervous system disorders (omalizumab 27.2% vs. placebo 25.0%) and in all cases but one (skin and subcutaneous tissue disorders: omalizumab 13.2% vs. placebo 20.4%) were in favor of omalizumab.
  • Table 8 Study D01. Number (%) of patients with treatment emergent adverse events (AEs), by preferred term (>5% in either treatment group, safety sample)
  • the population of this analysis is that of the study D01 as described above.

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Abstract

La présente invention concerne des procédés permettant de traiter des troubles associés à l'IgE et des produits prévus pour être administrés selon ces procédés. Ces procédés consistent à administrer à un sujet une quantité d'une première composition comprenant un antigène immunogène et une quantité d'une deuxième composition qui inhibe l'activité d'IgE. Ces procédés sont particulièrement utiles pour traiter des allergies comme des rhinites allergiques. Ces procédés présentent des avantages significatifs comme l'amélioration de l'efficacité de la thérapie tout en présentant un bon profil d'innocuité.
PCT/EP2001/005412 2001-05-11 2001-05-11 Compositions permettant de traiter les troubles associes aux ige WO2002092125A1 (fr)

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CA002446108A CA2446108A1 (fr) 2001-05-11 2001-05-11 Compositions permettant de traiter les troubles associes aux ige
EP01940460A EP1390067A1 (fr) 2001-05-11 2001-05-11 Compositions permettant de traiter les troubles associes aux ige
US10/476,263 US20050031609A1 (en) 2001-05-11 2001-05-11 Compositions for use in treating ige-associated disorders
CNA018232426A CN1507353A (zh) 2001-05-11 2001-05-11 用于治疗IgE相关性疾病的组合物
JP2002589041A JP2004529180A (ja) 2001-05-11 2001-05-11 ＩｇＥ関連障害を処置するのに使用するための組成物
PCT/EP2001/005412 WO2002092125A1 (fr) 2001-05-11 2001-05-11 Compositions permettant de traiter les troubles associes aux ige
BR0117009-0A BR0117009A (pt) 2001-05-11 2001-05-11 Composiçoes para utilização no tratamento de distúrbios associados a ige

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JP2007505911A (ja) * 2003-09-17 2007-03-15 ベイビー・ブースト，インコーポレイテッド アレルギーを予防する方法および装置
JP2007509164A (ja) * 2003-10-23 2007-04-12 カイロン コーポレイション 安定化組成物

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US20050026881A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anti-IgE antibody for treatment of asthma or chronic obstructive pulmonary disease
US20090263381A1 (en) * 2003-07-31 2009-10-22 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anti-ige antibody for treatment of asthma or chronic obstructive pulmonary disease
JP2006137678A (ja) * 2004-11-10 2006-06-01 Shionogi & Co Ltd インターロイキン−２組成物
WO2007095230A2 (fr) * 2006-02-13 2007-08-23 The Trustees Of The University Of Pennsylvania TRAITEMENT DE MALADIES BULLEUSES AUTO-IMMUNES A L'AIDE D'ANTICORPS ANTI-IgE
SG11201500889TA (en) 2012-08-21 2015-03-30 Sanofi Sa Methods for treating or preventing asthma by administering an il-4r antagonist
TWI697334B (zh) 2013-06-04 2020-07-01 美商再生元醫藥公司 藉由投與ｉｌ-４ｒ抑制劑以治療過敏及增強過敏原-特異之免疫療法的方法
TWI634900B (zh) 2013-07-11 2018-09-11 再生元醫藥公司 藉由投與ｉｌ－４ｒ抑制劑治療嗜酸性食道炎的方法
EP4353254A3 (fr) 2014-02-28 2024-07-03 Regeneron Pharmaceuticals, Inc. Méthodes de traitement d'une infection cutanée par administration d'un antagoniste d'il-4r
EP3218412A1 (fr) 2014-11-14 2017-09-20 Sanofi Biotechnology Méthodes de traitement de la sinusite chronique avec polypose nasale par administration d'un antagoniste d'il-4r
WO2018045130A1 (fr) 2016-09-01 2018-03-08 Regeneron Pharmaceuticals, Inc. Méthodes de prévention ou de traitement de l'allergie par administration d'un antagoniste d'il-4 r
WO2018057776A1 (fr) 2016-09-22 2018-03-29 Regeneron Pharmaceuticals, Inc. Méthodes de traitement d'une dermatite atopique sévère par administration d'un inhibiteur des il-4r
TWI784988B (zh) 2016-12-01 2022-12-01 美商再生元醫藥公司 治療發炎症狀的方法
WO2019028367A1 (fr) 2017-08-04 2019-02-07 Regeneron Pharmaceuticals, Inc. Méthodes de traitement de l'oesophagite à éosinophiles active
PL3703818T3 (pl) 2017-10-30 2024-03-25 Sanofi Biotechnology Antagonista IL-4R do zastosowania w sposobie leczenia lub zapobiegania astmie
WO2019222055A1 (fr) 2018-05-13 2019-11-21 Regeneron Pharmaceuticals, Inc. Méthodes de traitement de la dermatite atopique par administration d'un inhibiteur de l'il-4r
BR112021018627A2 (pt) 2019-03-21 2021-11-23 Regeneron Pharma Combinação de inibidores da via de il-4/il-13 e ablação de células plasmáticas para o tratamento de alergia
CA3147113A1 (fr) 2019-08-05 2021-02-11 Regeneron Pharmaceuticals, Inc. Methodes de traitement de la dermatite atopique par administration d'un antagoniste de l'il-4r
MX2022001030A (es) 2019-08-05 2022-04-26 Regeneron Pharma Metodos para tratar alergia y mejorar la inmunoterapia especifica de alergenos mediante la administracion de un antagonista de il-4r.
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JP2007505911A (ja) * 2003-09-17 2007-03-15 ベイビー・ブースト，インコーポレイテッド アレルギーを予防する方法および装置
JP2007509164A (ja) * 2003-10-23 2007-04-12 カイロン コーポレイション 安定化組成物
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WO2005100995A3 (fr) * 2004-04-06 2006-11-16 Sinai School Medicine Methodes permettant de determiner une reaction allergene au moyen de techniques de dosage immunologique realises au moyen de jeux ordonnes de microechantillons

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